Diet plays an important role in Parkinson's disease

Parkinson’s disease is one of the most common progressive systemic neurodegenerative disorders, affecting millions of people worldwide. Despite intensive research, the cause of neurodegeneration is not fully understood, so the current state of research assumes a multifactorial etiology. In addition to sporadic forms of genetic predisposition, environmental factors, including diet, play a crucial role. Gastrointestinal symptoms are often the first nonmotor symptoms in Parkinson’s disease, in addition to olfactory dysfunction, which in most cases occur years to decades before the first motor symptoms, i.e., rigor, tremor, and akinesis. Parkinson’s disease incidence rates are rising, it has been linked to the shift in the consumption of Western-style diets since the 1980s'. Growing evidence supports the idea that microbial dysbiosis and a proinflammatory intestinal environment are central components of the pathogenesis of Parkinson’s disease. It's some time that on online forums (the "grey literature") Parkinson's patients say that using butyric acid greatly improved their symptoms. Butiric acid is one of the height SCFAs. Short-chain fatty acids are a major group of metabolites involved in the microbiome-gut interaction and are produced through the anaerobic fermentation of dietary fibers. SCFAs have been investigated as having a possibly positive effect on several neurodegenerative diseases. As for any powerful nutrient, SCFAs may have uncomfortable side effects.

In Parkinson’s disease patients, the levels of SCFA-producing bacteria and fecal SCFAs are significantly reduced.

In a recent study investigating the potential therapeutic effect of propionate, the authors observed a putative neuroprotective effect in addition to immune regulation. Consumption of prebiotic fibers has recently been tested in a small cohort of Parkinson’s disease patients over 10 days. However, SCFA supplementation in Parkinson’s disease patients over a prolonged period has not yet been evaluated. In this pre-print article, the authors conducted an impressive clinical study over 6 months to investigate direct supplementation of the SCFAs propionate and butyric acid (butyric acid) and the prebiotic 2′-fucosyllactose. This study was supported by BASF Nutrition & Health Division.

There were three arms: * propionate+butyric acid capsules (butyric acid: 2550 mg; propionate: 1260 mg) with 2400 mg placebo, * 3250 mg 2' fucosyllactose capsules with 3200 mg placebo * 3250 mg 2' fucosyllactose capsules with 3810 mg propionate+butyric acid capsules daily for up to 6 months in combination with existing PD-specific therapy. 2'-fucosyllactose is an oligosaccharide. It is the most prevalent human milk oligosaccharide (HMO) naturally in human breast milk. 2'-fucosyllactose protects against infectious diseases, it also stimulates the growth of specific bifidobacteria. 2' fucosyllactose is known to protect against Campylobacter jejuni, Salmonella enterica serotype Typhimurium, Helicobacter pylori, etc. The capsules were provided by BASF.

The primary endpoints of this study were the impact on microbiome diversity and composition as well as changes in SCFA concentration in stool and serum. The secondary endpoints were the effect on the clinical parameters defined by The Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS III), levodopa equivalent daily dose (LEDD), PANDA, and olfactory score.

The study was performed from November 2019 to August 2020. This clinical trial was registered in the German Clinical Trials Register (DRKS; registration number DRKS00027061). A total of 72 participants were randomized and assigned to one treatment group upon recruitment.

Individual subjects were seen at the outpatient clinic every 3 months after initiation of supplementation and underwent a complete neurological assessment performed by a certified neurologist.

Improved clinical outcome upon 6 months supplementation in Parkinson’s disease patients.

Supplementation was generally well tolerated. All three interventions (treatments) globally led to a decrease (so an improvement in Parkinson's disease symptoms) in MDS-UPDRS III scores and LEDD over 6 months. This means that the patient's motor function improved, and they needed less medication. Yet in every intervention group, there were few patients with unchanged or increasing MDS-UPDRS III scores over time. Each group on average improved by seven points on MDS-UPDRS III scores, amazingly the improvement was more pronounced for patients who had high scores (patients who were in worst conditions). Yet an improvement of seven points on a scale which has 260 points is very minor.

Improvement in the sense of smell (olfaction) was only observed in the group that received 2' fucosyllactose and the combination group (2' fucosyllactose+butyric acid+propionate).

Cognitive function globally improved in all groups, as indicated by positive results in the PANDA test.

To gain insight into the mechanisms underlying successful SCFA intervention, the authors combined all 3 intervention groups and stratified them into responders (R: MDS-UPDRS III V2 < MDS-UPDRS III baseline) and nonresponders (NR: MDS259 UPDRS III V2 ≥ MDS-UPDRS III baseline). The scientists then selected the 20% of patients with the lowest and highest front numbers and sorted them into two clusters. These clusters included patients with the best/worst responses to intervention.

Scientist's analysis revealed that Streptococcus sp001556435 and Agathobacter rectalis contributed to the prediction of nonresponders, whereas SFEL01 sp004557245 had a significant impact on the prediction of responders. Agathobacter rectalis is a SCFA-producing bacterium.

In summary, SCFA supplementation may be a promising disease-modifying strategy in Parkinson’s disease, hence, a follow-up phase III clinical trial to investigate the therapeutic potential of SCFAs in Parkinson’s disease is warranted. Yet it's hard to see how a so minor improvement would lead to a market agreement. Another question is how this improvement scales with time, does it persist, does it improve further, or on the contrary, does this effect disappear?

Discuss it on the Parkinson's disease forum

Oral tauroursodeoxycholic acid (TUDCA) is a dietary supplement and medication for the treatment of primary biliary cirrhosis. It is currently being tested in patients with amyotrophic lateral sclerosis (ALS), alone or in combination with sodium phenylbutyrate (Relyvrio/AMX0035). It is also used in traditional Chinese medicine.

Current evidence indicates a protective effect of TUDCA in ALS, alone or in combination with phenylbutyrate (PB) at doses of 2000 mg/day.

Phenylbutyrate alone was tested in a phase II clinical study in 2009 for ALS, but the results appear to have been negative. On the contrary, TUDCA has been evaluated in clinical trials in the United States (2010) and South Korea (2012) and is approved in South Korea for the treatment of patients with amyotrophic lateral sclerosis. However, gastrointestinal adverse events are common.

Italian scientists became interested and carried out their own clinical trial in 2015. The results were very encouraging. It appears that Italian patients subsequently often took TUDCA in a controlled manner. As ALS is an incurable disease, the Emilia-Romagna Regional Health System (ERR) supports the off-label use of treatments that have shown promising evidence in early clinical studies. In this context, since 2015, TUDCA has been prescribed by specialized ALS centers operating in ERR, which participate in the ERR ALS register.

This recent Italian study aimed to determine, in a real-world setting, whether TUDCA had an impact on the overall survival of ALS patients treated with this drug compared to patients who received only standard care.

This propensity score-matched study was conducted in the Emilia-Romagna region. A propensity score-matched cohort study aims to reduce the impact of confounding variables (factors that could skew results) by matching subjects into two groups based on their propensity scores. Propensity scores are calculated to mimic the randomization of subjects, characteristic of double-blind clinical studies. However, propensity scores are defined by researchers, biases may exist. In a double-blind clinical study, researchers and participants do not know who is receiving the treatment and who is in the control (placebo) group. This blinding aims to eliminate bias and ensure that the results are objective.

In practice, clinical trials are often outsourced and are not as rigorous as they seem in theory. Additionally, companies and sponsors typically attempt to distort unsuccessful results by performing unscientific post-hoc analyzes and shifting the focus to obscure biomarkers. In addition, patients lie, how can we know that we have a 1 in 2 chance of being in the placebo arm without also taking supplements just in case? Thus, a propensity score matched study should certainly not be dismissed on the grounds that it is not a double-blind clinical study.

Of 627 ALS patients diagnosed between January 1, 2015 and June 30, 2021 and recorded in the registry with available death/tracheostomy information, 86 patients took TUDCA and were matched in a 1:2 ratio with 172 patients who received only usual care.

This matching (propensity scores) was performed based on age at onset, sex, phenotype, latency to diagnosis, ALS Functional Rating Scale-Revised (ALSFRS-R) at first visit, rate of disease progression at first visit, and BMI at diagnosis. The primary endpoint was the difference in survival (time from symptom onset to tracheostomy/death) between patients exposed to TUDCA and those not exposed.

TUDCA-exposed patients were then stratified based on dosage (less than or equal to 1000 mg/day or more) and duration (less than or equal to 12 months or more) of treatment. Median overall survival was 49 months in those treated with TUDCA and 36 months in the control group. This increase in survival is double that provided by Relyvrio/AMX0035. There was a reduced risk of death observed in patients exposed to a higher dosage (defined as ≥ 1000 mg/day) of TUDCA compared to both the control group and those with lower TUDCA dosages.

TUDCA was generally well-tolerated, except for a minority of patients (n = 7, 8.1%) who discontinued treatment due to side effects, primarily gastrointestinal and mild in severity; only 2 adverse events required hospital access so beware of strong doses of TUDCA on the long term.

There is an ongoing phase III clinical trial of TUDCA in Europe (NCT03800524), its results will probably be available in early 2024.

It's well recognized that physical activity plays a very important role for patients with Parkinson's disease. It may be responsible for systemic and in particular neuronal plasticity, but there is little scientific research on this topic. Indeed, during physical activity, a number of myokines and metabolites are released into the bloodstream, many of which can cross the blood-brain barrier and exert effects on the central nervous system.

Research has demonstrated that physical activity not only prevents cognitive decline and the risk of dementia in older adults and other neurodegenerative diseases, but also alleviates motor deficits, and alleviates neurological impairments.

Furthermore, recent studies have indicated that intensive and cognitively demanding programs can induce plastic changes in the brain in people with Parkinson's disease. In healthy subjects, the beneficial effects induced are mediated by an improvement in mitochondrial function and mitophagy.

This is relevant since mitochondrial dysfunction is a key phenomenon associated with early-onset Parkinson's disease, which occurs before the onset of motor symptoms.

Indicators of the neurodegenerative process of Parkinson's disease can be detected in the fibroblasts of patients with Parkinson's disease. Recent studies examining skin fibroblasts from patients with Parkinson's disease have indeed revealed metabolic and mitochondrial abnormalities.

The PARKEX trial is an open-label randomized clinical trial.

The PARKEX study is the first clinical trial that aims to evaluate the effects of two programs on the mitochondrial function of skin fibroblasts from patients with Parkinson's disease, as well as their impact on motor function, quality of life, sleep, cognitive aspects, and mood.

Two different physical activity and cognitive programs are designed to study the effect on mitochondrial function in skin fibroblasts from patients with Parkinson's disease. The first group will undergo basic physical training focused on strength and resistance. The second group will participate in exercises combined with motor and cognitive exercises. Participants will have to adapt to complex motor execution tasks. A third group, the sedentary group, will serve as a control. The intervention in both programs will last 3 months. The interventions will be carried out in groups, with 8 patients per group, and each session will last 60 minutes. The intervention programs will be structured in 3 cycles of 4 weeks. From the third week onwards, the workload will gradually increase.

In both physical activity programs, the exercises will target large muscle groups. Depending on the resistance put in place and the exercises, different muscles can be worked concentrically and eccentrically: lower limbs, upper limbs, and trunk. The Exxentric kBox4 device will be adapted with special harnesses, wall anchors, and support bars, depending on the patient's needs.

In addition to the main muscle groups, special attention will be given to key muscles involved in the gait cycle, such as the tibialis anterior, medial gastrocnemius, rectus femoris, and hamstrings, from a biomechanical perspective. This aspect will be common to both programs, the only difference being that the physical activity program will have a greater workload than the group with motor and cognitive exercises.

Hopefully, the implementation of functional programs and exercises over 12 weeks should have a positive impact on mitochondrial function. These improvements should translate into potential neuroprotective effects.

Discuss it on the Parkinson's disease forum

As there is little interesting news in neurodegenerative research, here is a low-quality review on one of my favorite topics and possibly a better article. You may remember that in early 2019 I made a plea for a TDP-43 genetic therapy. I wrote to roughly 250 scientists in this field, and only a handful responded. I may have absolutely no influence, but it seems to me there was more research in this area in the following years.

TDP-43 proteinopathies are pathological hallmarks in ALS/FTD. In general, aging is a risk factor for ALS/FTD adult-onset neurodegenerative diseases (NDD), as with aging comes protein misfolding and accumulation. Academics differentiate these diseases from the type of protein (or protein fragment) and the localization. In patients these distinctions do not hold: Every aging person has misfolded mislocated proteins of several kinds at the same time, so there is no pure sporadic Alzheimer's or Parkinson's diseases, or ALS. For example, scientists tell of three forms of demence that are linked to TDP-43 (FTD/FTLD, Limbic-predominant age-related TDP43 encephalopathy (LATE), and Hippocampal sclerosis of aging).

Now I think that abnormal cellular stress response, including ER stress, causes misfolded, mislocated protein aggregation so removing those deleterious protein aggregates would not really help. Just look at the 20 years of drug trials to remove amyloïds from the brains of Alzheimer patients.

Yet in this review they are still in this mindset, but they do not look after a genetic therapy, instead, the scientists explore small molecule-based approaches to enhance the clearance of pathological TDP-43.

Small molecule-based approaches are easier to implement and anyway, it fits well the academic agenda: To publish low-cost papers during one semester. There is nothing new in the list of drugs the authors list, and they lump in the same basket many unrelated drugs.

Another article is more interesting.

The authors recognize that endoplasmic reticulum (ER) is crucial for maintaining cellular homeostasis, and the synthesis and folding of proteins and lipids. The ER is the ordered membranous network and the first compartment of the secretory pathway, which is responsible for the synthesis, modification, and delivery of biologically active proteins to their proper target sites within the cell cytoplasm and the extracellular milieu. The ER is the entry site for the majority of proteins processed in the secretory pathway. If the influx of nascent, unfolded polypeptides exceeds the folding and/or processing capacity of the ER, the normal physiological state of the ER is perturbed. ER is sensitive to stresses including viral infection, it reduces its processing capability, and results in the accumulation of unfolded/misfolded proteins.

Generation of ER stress and induction of the unfolded protein response (UPR) are generic host responses to flavivirus infection as virus replication occurs in close association with ER-derived membranes. Flaviviruses include Dengue virus, Zika, and Japanese Encephalitis virus (JEV).

Then the authors boldly link UPR activation to inflammation. Then they tell that CXCR3 in linked to inflammation. They then assume that inhibiting CXCR3 would be somewhat beneficial to alleviate UPR activity, and therefore be beneficial to patients. I have a hard time finding this as an example of clear logical reasoning, but at least these guys have done some experiments.

They investigated the molecular insights of replication and inflammation upon Japanese encephalitis(JEV) infection and how AMG487 is rescuing it. In response to this, the authors studied the UPR activation pathways leading to ER stress and the rescue effect of AMG487. AMG487 treatment decreased the phosphorylation of eIF2α, a unique ER stress marker. AMG487 treatment improved ROS-induced inflammation and cell death in JEV-infected mice brains. It's already known that Antagonists to CXCR3 including AMG487 can be useful for treatment against flaviviruses, the novelty here is that AMG487 might decrease UPR activity.

Several ongoing efforts are to design and test drugs targeting cellular stress in ALS. The reasoning is that in ALS there is an abnormally prolonged cellular stress response that nearly stops the cell activity (because of lack of nutrients, including because of insulin resistance) and therefore creates a kind of traffic jam at the entrance of the Endoplasmic Reticulum. This would nicely explain why unfolded proteins are found in the cytoplasm of Central Nervous System cells. Yet it's been known for a long time that granules are formed when cells encounter a stress event. Stress granules disappear as soon as the cell resumes its normal functioning.

Scientists in Japan wanted to know if TDP-43 unfolded, mislocalized aggregations have some relation with stress granules. TDP-43 is an RNA-binding protein with various functions in RNA metabolism.

Previous studies have proposed a connection between TDP-43 inclusions and stress granules as often they colocalize.

This study investigated this relationship by examining the presence of a stress granule marker protein called HuR in ALS patients' anterior horn cells (AHCs). It included cases of sporadic ALS with different disease durations, comparing them to normal controls. The results showed a decrease in HuR immunoreactivity in AHCs of ALS patients, especially in standard-duration cases.

Furthermore, the study found that TDP-43 inclusions appear to have their origins in structures resembling stress granules, especially during the early stages of inclusion formation. These structures, termed DPCS (dot-like punctate cytoplasmic structures), were found to be HuR-positive and associated with the ribosome-like structures near the endoplasmic reticulum.

In conclusion, this research suggests that TDP-43 aggregation in ALS may begin with the involvement of stress granules. Understanding these early events may have implications for future ALS therapies.

While this research is not making huge claims (contrary to most low-quality scientific publications) it will certainly help to fund drug development for helping cells recover from abnormal cellular stress response.

There's a new post on one of my favorite topics: ER (endoplasmic reticulum) stress and ALS. If ER stress becomes chronic, as it does in many neurological diseases, it can cause proteins to misfold and accumulate in the cytosol, exactly what is found in ALS.

There are already drugs that target ER stress in ALS, for example Sephin1 also known as IFB-088 or icerguastat. https://inflectisbioscience.com/our-pipeline/

This new publication comes from an independent group in Finland.

One of the interesting aspects of this work is that they tested their drug candidate on 3 types of animal models (a fast TDP-43 model and a slow model, 1 SOD1). However, TDP-43 animal models are not commercial and it is therefore impossible to quickly reproduce their results. As usual with ALS animal models, the mice die quickly which does not reflect the human disease.

The authors used transgenic technology to produce brain dopamine neurotrophic factor (CDNF) in vivo. Activation of the transgene was as usual conditioned on the withdrawal of doxycycline in the diet. The method of administration was quite intrusive and would be difficult to replicate in human patients. A continuous infusion of 6 µg/day of CDNF or phosphate-buffered saline (PBS) as vehicle into the lateral ventricle of the brain (where the motor neurons are located).

Neurotrophic factors support the survival of dopamine neurons. Brain dopamine neurotrophic factor (CDNF) is a novel neurotrophic factor with strong trophic activity on dopamine neurons comparable to that of glial cell line-derived neurotrophic factor (GDNF). It is often cited in articles on Parkinson's disease. The CDNF protein is found primarily in the endoplasmic reticulum (ER) of cells. ER is an important cellular organelle primarily involved in the folding of approximately one third of all proteins in the cell. The authors' claims are impressive: "We found that administering CDNF to ALS mice and rats significantly improved their motor behavior and stopped the progression of paralysis symptoms. The improvement in symptoms was reflected in an increased number of surviving motor neurons in the spinal cord. spinal cord of animals compared to rodents that did not receive “CDNF. Our experiments suggest that CDNF could rescue motor neurons by reducing the ER stress response and, consequently, cell death. Importantly, ER stress was present in all of our animal models, regardless of specific genetic mutations,” explains study lead author Dr. Francesca De Lorenzo.

However, if we read the text carefully, only one animal model (SOD1) showed benefits, and the progression was slowed by 8 days or about a year for a human, which is an impressive result.

• In SOD1-G93A mice, the median survival time for females was 148 days for CDNF-treated mice and 140 days for PBS-treated mice, with an increase of 8 days. In males, median survival was 140.5 days for CDNF-treated mice and 132 days for PBS-treated mice, with an increase of 8.5 days. This likely corresponds to SOD1-G93A mice treated daily with riluzole in drinking water.

• Based on the text and supplementary materials, it appears that there was no benefit in survival time for either TDP-43 mouse models.

Yet, and this is a bit worrying, the abstract states "We show that intracerebroventricular administration of brain dopamine neurotrophic factor significantly arrests disease progression and improves motor behavior in the TDP43-M337V and SOD1 rodent models -G93A amyotrophic lateral sclerosis."

Since most people only read the summary or popular science articles, they are misled.

With aging, T cells of the adaptive immune system are often exhausted and/or become senescent. People with dysfunctional T cells are at high risk of infections, cancer, chronic diseases, and possibly death.

A recently published text studies the relationship between inflammation, alterations in the immune system, and Alzheimer's disease (AD). While the common mindset is to wonder what causes diseases (beta-amyloids in the case of Alzheimer's disease), this text takes a more complex view. There are many studies showing a link between the immune system and Alzheimer's disease.

Inflammation has been observed in postmortem brain scans of Alzheimer's disease patients, as well as the presence of amyloid plaques and neurofibrillary tangles.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to have a lower risk of dementia or Alzheimer's disease in adults who use them periodically, although results from clinical trials with NSAIDs have been mixed.

There is also a link between cognitive changes and acute infections. Likewise, there is a link between chronic infections and long-term cognitive decline.

Human herpesviruses, particularly herpes simplex virus-1 (HSV-1) and human herpesvirus 6 (HHV6), are considered potential contributors to infection-related inflammation causing Alzheimer's disease.

Other pathogens such as Porphyromonas gingivalis, Chlamydia pneumoniae, and Toxoplasma gondii have been associated with the development of Alzheimer's disease due to their chronic nature.

Vaccinations against diseases such as influenza, shingles, and BCG have shown associations with decreased risk of Alzheimer's disease in various populations.

To understand how the peripheral immune system is altered, it is interesting to study an aging cohort at different stages of Alzheimer's disease development.

Jason M Grayson, Suzanne Craft, and their colleagues at the Winston-Salem School of Medicine therefore studied an aging cohort that had been evaluated for Alzheimer's disease pathology.

The authors observed major alterations in the peripheral innate immune system in the blood of members of the aging cohort. High-dimensional flow cytometry, amyloid PET imaging, and cognitive testing were used to identify changes in the innate and adaptive immune systems as amyloid pathology and cognitive symptoms developed.

Specific findings include differences in dendritic cell populations, T cell differentiation, and cytokine production in amyloid-positive participants, particularly those with mild cognitive impairment.

Mature T cells are considered immunologically naive until they encounter the specific peptide in the context of a human leukocyte antigen (HLA) molecule that their receptor recognizes. Once antigen recognition occurs, cells receive a proliferative signal that leads to a marked expansion of antigen-specific T cells and an inflammatory response.

Although many of these T cells undergo apoptosis after the initial response, others are rescued from immune retraction and persist as memory T cells. Memory T cells can respond rapidly to a novel antigen-specific challenge and persist in blood circulation for a long time.

When the scientists examined the adaptive immune system, amyloid-positive participants, regardless of cognitive status, had an increase in their CD3 T cells. Further analyses of CD4 and CD8 T cells revealed that members of the aging cohort had increased numbers of T cells with a more differentiated phenotype, compared to those with normal cognition. That is to say that there was either or both a lower production of naive T cells and a strong presence of T cells having been in contact with pathogens.

When T cell function was measured, the authors observed that T cells from members of the aging cohort had increased IFN-γ production compared to other participants.

IFN-γ, or type II interferon, is a cytokine essential for innate and adaptive immunity against viral, bacterial, and protozoal infections. This is consistent with anti-microbial activity, which is one of the many roles of β-amyloids.

IFN-γ is an important activator of macrophages and an inducer of the expression of major histocompatibility complex class II molecules (HLA in humans). Aberrant IFN-γ expression is associated with several autoinflammatory and autoimmune diseases.

Several studies have observed an increase in IFNγ associated with slower symptomatic progression in Alzheimer's disease.

The authors explain that members of the aging cohort had a major increase in the number of T cells lacking cytokine production after restimulation and expressed increased levels of PD-1 and Tox, suggesting that these are exhausted cells.

Programmed cell death protein 1 (PD-1) is a protein found on the surface of T and B lymphocytes that plays a role in the immune system's response to cells in the human body by downregulating the immune system and promoting self-tolerance by suppressing the inflammatory activity of T cells.

PD-1 protein prevents autoimmune diseases, but unfortunately it also sometimes prevents the immune system from killing cancer cells. Given the many links between infection, inflammation, and Alzheimer's disease, these results suggest two models in which T cells could be a driving force in Alzheimer's disease.

• In the first model, amyloid production is a response to latent infections in the periphery and brain by the multiple chronic pathogens that all humans carry. Individuals who have strong T cell functions control the replication of these pathogens and remain cognitively normal. This would explain why members of the aging cohort, who have the most functional T cells, still have high cognitive levels.

However in individuals who lose T cell function, chronic pathogens reactivate and overstimulate innate responses, particularly type I interferon production, potentially leading to cognitive impairment. The authors suggest that T cell rejuvenation by immune checkpoint inhibitors and other therapies could be a plausible ex vivo therapy for Alzheimer's disease. Indeed, testing of immune checkpoint inhibitors in the 5X FAD mouse model of Alzheimer's disease has yielded promising results.

• An alternative model posits that the production of cytokines by T cells while participants are cognitively normal leads to the development of cognitive impairment. This idea is supported by a recent study by Jorfi and colleagues.

The study suggests that rejuvenating T cell function could be a potential treatment for Alzheimer's disease, particularly cancer therapies may suggest a possibility. For example, the patient's rare and/or dysfunctional T cells could be rejuvenated ex vivo once by pre-selected neurotransmitters and/or neuropeptides, tested, and reinoculated into the patient's body as it is currently administrated to some cancer patients.

Those of you who have bought an infrared helmet to attenuate your Alzheimer's disease might be interested in using it at night.

Photobiomodulation is a non-pharmacological approach based on the use of red or near-infrared light that has shown very promising results in the therapy of Alzheimer's disease in pilot clinical and animal studies. The Food and Drug Administration (FDA) recognizes photobiomodulation as safe.

It was recently discovered that photobiomodulation effectively stimulates lymphatic removal of wastes and toxins, including amyloid-β, from the brain.

A lymphatic network of transparent vessels

The Italian anatomist Mascagni discovered the lymphatic network of transparent vessels in the brain meninges of humans in the eighteenth century. The meninges are the three membranes that envelop the brain and spinal cord. However, for two centuries the dogma was that the cerebrovascular basement membrane which envelops blood vessels in the brain, was a key pathway for protein clearance from the central nervous system.

After 2014, when meningeal lymphatic vessels were re-discovered in the meninges of rodents and humans along the main cerebral veins and the middle meningeal artery, a growing number of results clearly showed that meningeal lymphatic vessels are tunnels for clearance of β amyloid protein from the brain.

Photobiomodulation during deep sleep

Photobiomodulation during deep sleep may provide a better therapy for Alzheimer's disease than photobiomodulation during wakefulness. In a new publication, scientists studied why photobiomodulation during sleep would be more effective in Alzheimer's disease during sleep. Since the brain lymphatics vessels play an important role in the removal of β amyloid protein from the brain and this system is activated during sleep, the scientists tested their hypothesis that photobiomodulation can stimulate clearance of β amyloid protein from the brain via the lymphatics stronger during sleep vs. wakefulness. The authors found the presence of β amyloid protein in meningeal lymphatic vessels after its injection into the hippocampus. As the hippocampus is at the center of the brain, it means the β amyloid protein was moved from the center of the brain to its periphery. These results confirm other data suggesting that meningeal lymphatic vessels are the tunnels for lymphatic transport of β amyloid protein.

To further prove that the injury of lymphatic vessels significantly alters β amyloid protein evacuation from the hippocampus in mice, the scientists photo-ablated meningeal mice's lymphatic vessels with 5-ALA. 5-ALA is usually used to selectively destroy tissues. After this operation, photobiomodulation was used to verify if it could heal mice's lymphatic vessels

The evacuation of β amyloid protein from the hippocampus and its subsequent distribution in the meninges after photo-ablation of meningeal lymphatic vessels was higher in mice that received photobiomodulation during deep sleep than mice treated by photobiomodulation during wakefulness. These data clearly demonstrate that photobiomodulation-mediated restoration of brain lymphatic function contributing to the removal of β amyloid protein from the brain is more effective during deep sleep than in the waking state.

The photobiomodulation was performed with 3835 SMD LED (central wavelength 1050 nm and spectrum width of 50 nm). The LED was operated in continuous wave mode with an output power of 50 mW that was distributed over a 3.6 mm spot at the skull surface. The irradiance at the skull surface does not exceed 0.5 W/cm2. The dose for a single 17-minute procedure each day was 500 J/cm2.

Conclusion

Photobiomodulation as a non-invasive and safe approach has high prospects for implementation in clinical practice for the treatment of brain diseases associated with lymphatic disorders, such as Alzheimer's disease or Parkinson’s disease.

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